Despite the widespread PSA population screening, prostate cancer (PC) still ranks as the second leading cause of neoplastic deaths in men. The most vexing clinical issue has been overdiagnosis: since most asymptomatic men will harbor foci of PC in their prostate, but only a small fraction will die of the disease, widespread screening leads to many harms due to morbid treatment for disease that may never have become clinically apparent. Thus, active surveillance (AS) has emerged as an alternate strategy. However, the lack of reliable biomarkers of progression has presented a large obstacle to its uptake. What is critically needed is a new methodology that would prospectively distinguish indolent from aggressive PC on biopsies routinely obtained from patients on AS. The goal of this project is to develop such a technology. We will take advantage of the synergy among (i) field carcinogenesis as a biomarker source: not only prostate tumor cells but a much larger population of histologically normal cells throughout the prostate bear the fingerprint of risk. This better represents the natural history of the disease then assessing the tumor per se which comprises numerous clones. (ii) Cellular nanoarchitecture as a biomarker: Alterations in nanoscale morphology are the final common denominator for the molecularly heterogeneous carcinogenesis process. (iii) A new biophotonics technology, partial wave spectroscopic (PWS) nanocytology, which is currently the only technology capable of measuring intracellular nanoscale structure in a practical manner. Preliminary data from a double-blind study showed the potential of the nanocytological detection of field carcinogenesis in histologically normal prostate biopsies from patients with Gleason 6 disease as an accurate predictor of the future aggressiveness of prostate cancers. In this project we will test the hypothesis that PWS nanocytology of microscopically normal prostate tissue will be able to identify the risk of aggressive PC. We will develop a PWS nanocytology system adapted to acquire data on PC histological biopsy sections, identify new nanoscale architectural biomarkers to more accurately identify clinically significant PC, develop a robust protocol for processing and analysis of biopsies for nanocytology, and test the prediction rule in a prospective blinded study. We will enrich for African- Americans who suffer disproportionally from PC. This novel approach will be critical in bridging the era of personalized medicine to PC management. PWS nanocytology can be incorporated into AS protocols to analyze biopsies and predict subsequent progression of PC more accurately and at an earlier stage than is currently possible histologically. The approach can be coupled with existing AS protocols with no additional procedures, thus impacting upon clinical practice quickly. Our goal is that by the end of the project period, the technology will b developed, clinically tested and ready for FDA trials.